Martin Maiden on the Population Biology & Molecular Epidemiology of Meningococci

Special Topic of Meningitis Interview, September 2010

Martin MaidenMeningococcal disease is one of the more serious invasive diseases worldwide. The term is used to describe meningitis and septicemia caused by the bacterium Neisseria meningitidis, also known as meningococcus. There are five main groups of the bacterium, each of which has a unique outer coat that makes it difficult for the body's immune system to kill it.

Our Special Topics analysis of papers on meningococcal disease published over the past decade shows that the research being carried out by Professor Martin Maiden and his colleagues in the Department of Zoology at the University of Oxford ranks at #8 by total papers and #13 by total cites, based on 57 papers cited a total of 1,729 times.

In Essential Science IndicatorsSM from Thomson Reuters, Maiden's work ranks in the top 1% in the fields of Microbiology and Computer Science, with a total of 91 papers cited 3,646 times between January 1, 2000 and April 30, 2010.

Maiden's group has exploited nucleotide sequencing to investigate the population biology and evolution of pathogenic bacteria. European correspondent Simon Mitton spoke with Maiden about his interest in the bacteria responsible for infectious diseases.

SW: It's a pleasure for me to be back in Oxford, where I read physics in the late 1960s. But I'm here today to talk to you about zoology rather than physics. You did your B.Sc. at the University of Reading UK followed by a Ph.D. in biochemistry at Cambridge. What sparked your interest in the biology of infectious disease?

Whilst at high school I was inspired by Sir Frank Macfarlane Burnet's classic book Natural History of Infectious Disease and whilst at Reading my interest in the area was deepened by marvelous lectures on infectious diseases given by Professor Colin Kaplan, who had been involved in the eradication of smallpox.

On graduation I went to the Peter Henderson's laboratory in the Biochemistry Department, Cambridge, to gain experience in molecular techniques, which were just coming into microbiology and would clearly be influential. Following the award of the doctorate I held a two-year MRC training fellowship.

SW: After that you started work in a government laboratory. How did that influence your subsequent research career?

Moving to the National Institute for Biological Standards and Control (NIBSC), a global leader in assessing the quality of biological medicines, enabled me to start a research program on infectious disease. NIBSC wanted to develop a program on Neisseria meningitidis and I realized that I could use comparative sequence analyses, which I had learned in Cambridge, to study meningococcal surface proteins.

SW: When did you start to take gene sequencing seriously?

Shortly after I started at NIBSC I teamed up with Ian Feavers, who had a similar background and ideas, and since then we have collaborated extensively in applying evolutionary concepts to investigating immune interactions by comparative sequence analysis.

"We now have a good understanding about the population structure of meningococci and how it influences disease."

Some regard our approach as rather eccentric, but in my view it's no more controversial than using mouse models to study human immunity. Ian and I started our project of multiple sequencing at a time when direct nucleotide sequencing still presented challenges.

SW: A public health laboratory funded by government is probably not an ideal situation in which to conduct blue skies research. How did you move on?

I was fortunate to be awarded a Humboldt Fellowship to work at the Max Planck Institute for Molecular Genetics in Berlin with Mark Achtman. There I could fuse my interests in sequences with population biology concepts, and distilled them into the multilocus sequence typing (MLST) approach. Shortly after my return, I migrated to the Zoology Department at Oxford, with a Wellcome Trust Senior Fellowship sponsored by Brian Spratt. I've benefited from the strong emphasis on evolution and population dynamics that this department has.

SW: Before we look at your key papers, can you comment on the human impact of meningococcal disease?

In the period prior to the introduction of the MenC conjugate vaccine it was a major cause of death in young people in the UK. Today in sub-Saharan Africa it remains a major problem; about once a decade it reaches epidemic proportions, causing tens of thousands of deaths. Meningococcal septicemia is extremely dangerous: it develops rapidly, and is therefore a terrifying disease for parents because a healthy child can deteriorate to a life-threatening condition within hours.

SW: What is the main theme of the papers in the Special Topics analysis?

The puzzling thing about meningococcus is that it is ubiquitous; most people carry many meningococci harmlessly. These papers show the extent of diversity in meningococcal populations, but also that this diversity is structured.

There are 13 meningococcal serogroups, five of which are responsible for most cases of disease. These correspond to different capsular polysaccharides, which contributes towards virulence. Beneath that primary distinction, gene sequencing has elucidated a huge amount of genetic and further antigenic diversity. This has shown us that some groups are more likely to cause the disease than others.

What we have is a conundrum: an organism that is apparently a terrible pathogen but is actually a highly adapted commensal organism. So we have to ask the questions: Why does this normal commensal turn nasty, and why do only some variants turn nasty? That's a unifying theme in our research and the papers in this Special Topics analysis.

SW: Most of the papers in this decadal survey cite an earlier 1998 paper (Maiden MCJ, et al., "Multilocus sequence typing: A portable approach to the identification of clones within populations of pathogenic microorganisms," PNAS USA 95[6]:3140-5, 17 March 1998) on multilocus sequence typing (MLST), a technique that you and your colleagues invented.

Yes. The 1998 paper is important because it established a major paradigm for molecular epidemiology. We were fortunate that the Neisseria field had a group of us who had worked on different aspects of the problem, which is what you need for an innovative team. By getting the major players together our research was immediately acceptable to the Neisseria community. Our approach worked, enabling us to characterize microbial populations.

It triggered a cascade of MLST schemes for various bacteria, mainly but not exclusively pathogens. Many of our papers from the past decade are based on this approach. The typing of Campylobacter jejuni, for example, was a complete mess when we got into the field, but MLST analyses have given us a good idea of where it comes from.

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